Rilpivirine hydrochloride, chemically 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]pyrimidinyl]amino]benzonitrile hydrochloride and has the structural formula:

Rilpivirine (TMC278) is an investigational new drug, developed by Tibotec, for the treatment of HIV infection. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs.
Rilpivirine and its hydrochloride salt were disclosed in U.S. Pat. No. 7,125,879.
Process for the preparation of rilpivirine was disclosed in U.S. Pat. No. 7,399,856 ('856 patent). According to the '856 patent, rilpivirine can be prepared by reacting the (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride of formula II with 4-(4-chloropyrimidin-2-ylamino)benzonitrile of formula III-a in the presence of potassium carbonate and acetonitrile under reflux for 69 hours. The synthetic procedure is illustrated in scheme I, below:

According to the '856 patent, 4-(4-chloropyrimidin-2-ylamino)benzonitrile of formula III-a can be prepared by reacting the 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile with phosphorus oxytrichloride in the presence of methylene chloride and 2-propanone.
Process for the preparation of rilpivirine was disclosed in U.S. Pat. No. 7,705,148 ('148 patent). According to the '148 patent, rilpivirine can be prepared by reacting the 4-[[4-[[4-bromo-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile with acrylonitrile in the presence of palladium acetate, N,N-diethylethanamine and tris(2-methylphenyl)phosphine in acetonitrile.
According to the '148 patent, rilpivirine can be prepared by reacting the compound of formula IV with 4-(4-chloropyrimidin-2-ylamino)benzonitrile formula III-a in the presence of hydrochloric acid and n-propanol to obtain a compound of formula VII, and then the compound was treated with acetonitrile and potassium carbonate under reflux for 69 hours. The synthetic procedure is illustrated in scheme II, below:

According to the '148 patent, 4-(4-chloropyrimidin-2-ylamino)benzonitrile of formula III-a can be prepared by reacting the 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile with phosphorus oxytrichloride in the presence of methylene chloride and 2-propanone.
U.S. Pat. No. 7,563,922 disclosed a process for the preparation of (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride. According to the patent, (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride can be prepared by reacting the 4-iodo-2,6-dimethyl-benzenamine in N,N-dimethylacetamide with acrylonitrile in the presence of sodium acetate and toluene, and then the solid thus obtained was reacted with hydrochloric acid in 2-propanol in the presence of ethanol and diisopropyl ether.
An unpublished application, IN 1415/CHE/2011 assigned to Hetero Research Foundation discloses a process for the preparation of rilpivirine. According to the application, rilpivirine can be prepared by reacting the 4-(4-chloropyrimidin-2-ylamino)benzonitrile with (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride in the presence of p-toluene sulfonic acid monohydrate and 1,4-dioxane.
It has been found that the rilpivirine produced according to the prior art procedures involves higher number of chemical steps and results in low yields. According to the present invention rilpivirine can be obtained in higher yields and in fewer number of reaction steps than the prior art processes.
We have found a novel process for the preparation of rilpivirine and its pharmaceutically acceptable acid addition salts thereof using novel intermediate.
The process of present invention is simple, inexpensive and reproducible and is well suited on an industrial scale.
Thus, an object of the present invention is to provide a novel process for preparing rilpivirine and pharmaceutically acceptable acid addition salts thereof in high yields using novel intermediate.